1 INDICATIONS AND USAGE TYGACIL is a tetracycline class antibacterial indicated in patients 18 years of age and older for: • Complicated skin and skin structure infections ( 1.1 ) • Complicated intra-abdominal infections ( 1.2 ) • Community-acquired bacterial pneumonia ( 1.3 ) Limitations of Use : TYGACIL is not indicated for treatment of diabetic foot infection or hospital-acquired pneumonia, including ventilator-associated pneumonia ( 1.4 ).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections that are proven or strongly suspected to be caused by bacteria ( 1.5 ).

1.1 Complicated Skin and Skin Structure Infections TYGACIL is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp.

(includes S.

anginosus, S.

intermedius, and S.

constellatus ), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

1.2 Complicated Intra-abdominal Infections TYGACIL is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp.

(includes S.

anginosus, S.

intermedius, and S.

constellatus ), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

1.3 Community-Acquired Bacterial Pneumonia TYGACIL is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae , and Legionella pneumophila .

1.4 Limitations of Use TYGACIL is not indicated for the treatment of diabetic foot infections.

A clinical trial failed to demonstrate non-inferiority of TYGACIL for treatment of diabetic foot infections.

TYGACIL is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia.

In a comparative clinical trial, greater mortality and decreased efficacy were reported in TYGACIL-treated patients [see Warnings and Precautions (5.2) ].

1.5 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline.

TYGACIL may be initiated as empiric monotherapy before results of these tests are known.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1) ] • Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2) ] • Anaphylaxis [ Warning and Precautions (5.3) ] • Hepatic Adverse Effects [ Warnings and Precautions (5.4) ] • Pancreatitis [ Warnings and Precautions (5.5) ] The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.

at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with TYGACIL.

TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators.

Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1.

Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies Body System Adverse Reactions TYGACIL (N=2514) Comparators Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.

(N=2307) Body as a Whole Abdominal pain 6 4 Abscess 2 2 Asthenia 3 2 Headache 6 7 Infection 7 5 Cardiovascular System Phlebitis 3 4 Digestive System Diarrhea 12 11 Dyspepsia 2 2 Nausea 26 13 Vomiting 18 9 Hemic and Lymphatic System Anemia 5 6 Metabolic and Nutritional Alkaline Phosphatase Increased 3 3 Amylase Increased 3 2 Bilirubinemia 2 1 BUN Increased 3 1 Healing Abnormal 3 2 Hyponatremia 2 1 Hypoproteinemia 5 3 SGOT Increased LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

4 5 SGPT Increased 5 5 Respiratory System Pneumonia 2 2 Nervous System Dizziness 3 3 Skin and Appendages Rash 3 4 In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs.

In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients (see Table 2 ).

The cause of the imbalance has not been established.

Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2.

Patients with Outcome of Death by Infection Type TYGACIL Comparator Risk Difference The difference between the percentage of patients who died in TYGACIL and comparator treatment groups.

The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.

Infection Type n/N % n/N % % (95% CI) CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.

Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

cSSSI 12/834 1.4 6/813 0.7 0.7 (-0.3, 1.7) cIAI 42/1382 3.0 31/1393 2.2 0.8 (-0.4, 2.0) CAP 12/424 2.8 11/422 2.6 0.2 (-2.0, 2.4) HAP 66/467 14.1 57/467 12.2 1.9 (-2.4, 6.3) Non-VAP These are subgroups of the HAP population.

41/336 12.2 42/345 12.2 0.0 (-4.9, 4.9) VAP 25/131 19.1 15/122 12.3 6.8 (-2.1, 15.7) RP 11/128 8.6 2/43 4.7 3.9 (-4.0, 11.9) DFI 7/553 1.3 3/508 0.6 0.7 (-0.5, 1.8) Overall Adjusted 150/3788 4.0 110/3646 3.0 0.6 (0.1, 1.2) Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.

An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively.

The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%).

Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%).

Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions (5.10) ] .

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy.

The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity.

In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam.

In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin.

In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from TYGACIL was most frequently associated with nausea (1%) and vomiting (1%).

For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole : injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System : thrombophlebitis Digestive System : anorexia, jaundice, abnormal stools Metabolic/Nutritional System : increased creatinine, hypocalcemia, hypoglycemia Special Senses : taste perversion Hemic and Lymphatic System : prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages : pruritus Urogenital System : vaginal moniliasis, vaginitis, leukorrhea 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of TYGACIL.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

• anaphylactic reactions • acute pancreatitis • hepatic cholestasis, and jaundice • severe skin reactions, including Stevens-Johnson Syndrome • symptomatic hypoglycemia in patients with and without diabetes mellitus • hypofibrinogenemia [see Warnings and Precautions (5.6) ]